This proposal describes a 5-year training program for the development of an academic career in Clinical Pathology. The candidate is completing residency training in clinical laboratory medicine at Harvard Medical School, Boston, and now proposes to expand his scientific background and skills in research of basic immunobiology and immunology of infectious diseases. The program will provide mentored research in the area of CD1 antigen presentation and T cell function in the laboratory of the sponsor, Dr. Michael Brenner, Chief of the Division of Rheumatology, Immunology and Allergy at Brigham and Women's Hospital, Boston, who is a recognized leader in the field of CD1 biology. Dr. Brenner has an outstanding record of successfully training clinician scientists. In order to allow successful training in and completion of the B cell biology aspect of the proposal, Dr. Shiv Pillai, a recognized expert in the field of B cell biology, will serve as co-mentor. In addition to the development of an independent project area, the complementation of the program with coursework, lectures, seminars and career mentoring will promote the candidate's development into an independent academic investigator. The proposed research project will investigate the function of Natural Killer T (NKT) cells, a specialized subset of T cells that recognizes CD1d-presented lipid and glycolipid antigens. NKT cells have been strongly implicated in host defense to microbial infection, however, little is known about both the mechanism of NKT cell activation during microbial infection and the interaction of NKT cells with other cells of the immune system during the generation of a successful protective immune response. We propose to examine the role and function of NKT cells during infection with the encapsulated pathogen Streptococcus pneumoniae. To investigate the mechanism of NKT cell activation during this infection, we will determine the role of TLR-mediated signaling, cytokine signaling and self-antigen recognition for NKT cell responses to S. pneumoniae (Aim 1). In addition, we will isolate lipids and lipidated polysaccharides from S. pneumoniae bacteria and determine whether these compounds can be recognized by NKT cells as cognate CD1d- presented antigens (Aim 2). Next, we will examine the role of NKT cells in generating a protective antibody response during S. pneumoniae infection, in particular to capsular polysaccharide antigens (Aim 3). These studies seek to address fundamental unanswered questions regarding the function of NKT cells in microbial immunity. This has significance for host defense to infection and other diseases. Infection with S. pneumoniae is a leading cause of illness and death in the United States. The proposed studies are important for understanding immunity to this pathogen and could lead to new strategies for immune protection and vaccine development.